The B1a (CD5+) B-cells are the primary producers of natural antibodies that are self-reactive and polyreactive but usually non-pathogenic. However, in some circumstances, B1a B-cells contribute substantially to the immunopathogenesis of chronic systemic autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome and systemic lupus erythematosus (SLE). B1a B-cells are a critical arm of the innate immune system and provides the first line of defense against a variety of bacterial and viral infections. The most prevalent B-cell malignancy, chronic lymphocytic leukemia (CLL) is CD5+ B-cell in origin. Curiously, HIV patients with progressive disease have paucity of CD5+ B-cells; in contrast, seropositive individuals with non-progressive disease have normal levels of B1a B-cells. This suggests the possibility that natural antibodies produced by CD5+ B-cells may be protective in HIV. The role of CD5 in the development, function and/or persistence of B1a B-cells remains an unresolved and controversial question. Since CD5 can negatively regulate signals initiated when the B-cell antigen receptor (BCR) is engaged by antigen, it is believed that its primary role in B1a B-cells is to control B-cell receptor activation from responding pathogenically to self antigen. However, this dogma is challenged by the fact that that CD5-/- mice do not develop spontaneous autoimmune disease. Our recent studies have led to that discovery that a major and probably dominant role of CD5, in addition to its inhibitory activity, is to promote survival. The survival activity of CD5 is mediated its unique interaction with CK2, a serine/threonine kinase that is a major positive regulator of multiple cellular prosurvival signaling cascades. In a counterpoint to the prosurvival activity mediated by activation of CK2, CD5 also has an immunoreceptor tyrosine inhibitory motif (ITIM) necessary for negative regulation of B-cell activation. The ITIM domain also provides prosurvival signals by attenuating B-cell activation and therefore activation-induced cell death. We suggest that CD5 regulates the B-cell response by two independent but complimentary pathways. To test this model, we have generated by gene targeting approach mice expressing CD5 with selective inability to activate the CD5-CK2 dependent prosurvival signaling cascade and mice lacking CD5-ITIM dependent negative regulatory activity. Using these unique animal models, and the new model we propose to develop, we will be in a position to (1) determine the role of CD5 in the development of B1a B-cells and its contribution to autoimmunity, (2) elucidate how CD5 regulates B-cell responses to T-independent antigens and T-dependent antigens and (3) dissect the molecular mechanism of CD5-dependent survival and inhibitory signals in normal B-cells. These studies using the novel animal models will enable us to resolve CD5 biology in B-cells. An important outcome of the proposed studies will be a major advancement in our understanding of regulatory pathways in innate B-cell responses to bacterial and viral pathogens and the development of targeting approaches for treatment of autoimmune diseases and leukemia. PUBLIC HEALTH RELEVANCE: CD5+ B-Cells (B1a) B-cells are important in innate immunity, shaping the adaptive immune repertoire and in the immunopathogenesis of autoimmune diseases. The role of CD5 in the development of B-cells has been extensively interrogated, but remains unresolved; the goal of this proposal is to fill this gap in our understanding.